Nonsynonymous HTR2C polymorphism predicts cortisol response to psychosocial stress I: Effects in males and females

• We examine effects of rs6318 on the cortisol response to lab-induced stress.
• We examine whether sex moderates the effects of rs6318 on the stress response.
• Participants provided DNA and completed a lab-induced stress or control protocol.
• C-carriers exhibited blunted cortisol responses compared to non C-carriers.
• We observed significant effects in both sexes without moderation by sex.

BackgroundGenetic influences on stress reactivity may provide insight into depression risk mechanisms. The C-allele of rs6318, a putatively functional polymorphism located within the HTR2C gene, has been reported to predict greater cortisol and negative affective reactivity to lab-induced stress. However, the potential moderating effect of sex has not been examined despite X-linkage of HTR2C. We hypothesized that sex moderates the effect of rs6318 on cortisol and affective reactivity to lab-induced stress, with males showing stronger effects.MethodsNon-depressed young adults (N = 112; 39 female) screened via clinical interview provided a DNA sample and completed either a negative evaluative Trier Social Stress Test, or a non-evaluative control protocol. Salivary cortisol and self-reported affect were assessed at four timepoints.ResultsContrary to hypotheses, C-carriers showed blunted rather than exaggerated cortisol responses to lab-induced stress in multilevel models (b = 0.467, p < 0.001), which persisted when covarying subclinical depressive symptoms. This effect was not moderated by sex (b = 0.174, p = 0.421), and remained significant when examining females (b = 0.362, p = 0.013) and males (b = 0.537, p < 0.001) separately. C-carriers also exhibited marginally greater reactivity in negative self-focused affect in response to stress than non-carriers when covarying subclinical depressive symptoms (b = -0.360, p = 0.067), and exhibited higher levels of subclinical depressive symptoms than non-carriers (F = 6.463, p = 0.012).ConclusionsResults support a role for the rs6318 C-allele in dysregulated stress responding, and suggest that the C-allele may contribute to risk for depression.